Mark A. Levine, MD

Chief of the Molecular and Clinical Nutrition Section,
Senior Investigator and Senior Staff Physician,
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Bethesda, MD

image of Dr. Mark Levine
Abstract: Recommended intakes for many vitamins are based on preventing deficiency, with a safety margin. Our hypotheses are that vitamin recommendations can and should be based on detailed, state-of- the-art physiology investigations in humans, using clinical tools of concentration-function relationships and pharmacokinetics, coupled to cell biology and genomics. Clinical investigation tools were used to characterize vitamin C physiology in healthy men and women, ages 18-28 years. Utilizing a depletion-repletion design, vitamin C concentrations were found to be tightly controlled in plasma and cells, over a dose range of 30 to 2500 mg. Tight control had at least 4 components: bioavailability, or intestinal absorption; tissue transport; renal filtration, or renal reabsorption/excretion; and utilization. The first three components were regulated by two tissue transporters, mediated by identified transporters SLC23A1 (SVCT1) and SLC23A2 (SVCT2), as well as by as yet unidentified transporters. Recent studies indicate that red blood cells are a unique tissue compartment for ascorbate. In contrast to other tissues, red blood cells transport dehydroascorbic acid (oxidized ascorbate), utilizing GLUT1. Bioavailability studies showed that percent intestinal absorption decreased as doses increased. Intravenous administration of doses above 100 mg produced ascorbate plasma concentrations that could not be achieved with oral dosing. These data indicated that, depending on dose and rate of administration, intravenous ascorbate produced pharmacologic plasma concentrations, with renal filtration restoring homeostasis. Pharmacologic intravenously administered ascorbate but not oral ascorbate had potential to decrease cancer growth in humans. Pharmacologic ascorbate was cytotoxic to cancer but not normal cells in vitro, in animals, and in small but encouraging studies in humans. Pharmacologic ascorbate mediated cancer cell death by generation of extracellular hydrogen peroxide (H2O2) in vivo. Pharmacologic ascorbate can be considered a pro-drug for delivery of pharmacologic H2O2 concentrations to the extracellular space. There are an ever-increasing multiplicity of downstream mechanisms of ascorbate-mediated cancer cell cytotoxicity that are H2O2-dependent. In specifically modified cell lines, mechanisms have been proposed that are H2O2-independent, for example based on dehydroascorbic acid. However, this mechanism does not appear to have general applicability. Clinically, pharmacologic ascorbate has a surprisingly strong safety profile. Non-specificity, or promiscuity, of many oncology therapeutics is often harmful because of collateral damage to normal tissues in humans. In contrast, benefit is provided to patients by the promiscuity of pharmacologic ascorbate because of its safety and potential efficacy. Accelerated ascorbate utilization occurs in critically ill patients. Using similar pharmacokinetics principles as for cancer treatment, intravenous ascorbate has shown recent promise in treatment of sepsis. Based on transporter principles and RBC physiology, ascorbate either orally or intravenously has additional promise in delaying complications of diabetic microvascular disease. Considered together, the data indicate that exhaustive characterization of vitamin physiology in healthy people serves as a gateway to advances in disease treatment and prevention. Applying this approach to other vitamins will provide physiologic bases for vitamin recommendations, and may reveal unanticipated application to disease treatment.